The Challenge of an Ever-Mutating Virus
By Stanford University
The virus that causes COVID-19 has continuously mutated, making it harder for existing antibody treatments to remain effective. Many treatments developed during the pandemic no longer work against newer variants. However, a team of researchers from Stanford University may have discovered a way to create longer-lasting therapies that can keep up with the virus’s evolution.
The team developed a method using two antibodies: one that
acts as an anchor by attaching to a stable part of the virus, and another that
blocks its ability to infect cells. In laboratory tests, this antibody pairing
successfully neutralized the original SARS-CoV-2 virus and all its variants,
including omicron. Their findings were published today (March 5) in Science
Translational Medicine.
“In the face of an ever-changing virus, we engineered a new generation of therapeutics that have the ability to be resistant to viral evolution, which could be useful many years down the road for the treatment of people infected with SARS-CoV-2,” said Christopher O. Barnes, the study’s senior author, an assistant professor of biology in the Stanford School of Humanities and Sciences and a scholar at Stanford’s Sarafan CheM-H.
An Overlooked Option
The team led by Barnes and first author Adonis Rubio, a
doctoral candidate in the Stanford School of Medicine, conducted this
investigation using donated antibodies from patients who had recovered from
COVID-19. Analyzing how these antibodies interacted with the virus, they found
one that attaches to a region of the virus that does not mutate often.
This area, within the Spike N-terminal domain, or NTD, had
been overlooked because it was not directly useful for treatment. However, when
a specific antibody attaches to this area, it remains stuck to the virus. This
is useful when designing new therapies that enable another type of antibody to
get a foothold and attach to the receptor-binding domain, or RBD, of the virus,
essentially blocking the virus from binding to receptors in human cells.
Designing a More Resilient Defense
The researchers designed a series of these dual or
“bispecific” antibodies, called CoV2-biRN, and in laboratory tests they showed
high neutralization of all the variants of SARS-CoV-2 known to cause illness in
humans. The antibodies also significantly reduced the viral load in the lungs
of mice exposed to one version of the omicron variant.
The Path Forward: Beyond COVID-19
More research, including clinical trials, would have to be
done before this discovery could be used as a treatment in human patients, but
the approach is promising – and not just for the virus that causes COVID-19.
Next, the researchers will work to design bispecific
antibodies that would be effective against all coronaviruses, the virus family
including the ones that cause the common cold, MERS, and COVID-19. This
approach could potentially also be effective against influenza and HIV, the
authors said.
“Viruses constantly evolve to maintain the ability to infect
the population,” Barnes said. “To counter this, the antibodies we develop must
continuously evolve as well to remain effective.”
Reference: “Bispecific antibodies targeting the N-terminal
and receptor binding domains potently neutralize SARS-CoV-2 variants of
concern” 5 March 2025, Science Translational Medicine.
DOI: 10.1126/scitranslmed.adq5720
Additional Stanford authors include biology undergraduate
Megan Parada; biology staff scientist Morgan Abernathy; life science researcher
Yu E. Lee; biology lab technician Michael Eso; biophysics doctoral student Gina
El Nesr; and former lab technicians Israel Ramos, Teresia Chen, and Jennie
Phung. Barnes is also affiliated with the Chan Zuckerberg Biohub.
Rubio, BS ’21, is also affiliated with the Department of
Biology in the School of Humanities and Sciences.
This work also includes co-authors from Rockefeller
University, Fred Hutchinson Cancer Center in Seattle, and the Howard Hughes
Medical Institute.
This research received support from the Chan Zuckerberg
Biohub, Howard Hughes Medical Institute, National Institutes of Health,
National Science Foundation, Pew Biomedical Scholars Program, and Rita Allen
Foundation.
Rockefeller University has filed a provisional patent
application in connection with monoclonal antibodies described in this work on
which co-authors Zijun Wang and Michel C. Nussenzweig of Rockefeller University
are inventors (U.S. patent 17/575,246). Co-authors Jesse D. Bloom of Fred
Hutchinson Cancer Center consults for Invivyd, Apriori Bio, the Vaccine
Company, GSK, and Moderna. Bernadeta Dadonaite, also of Fred Hutchinson Cancer
Center, consults for Moderna. Bloom and Dadonaite are inventors of Fred Hutchinson
Cancer Center-licensed patents related to viral deep mutational scanning.
